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Evidence for a single heptahelical domain being turned on upon activation of a dimeric GPCR
Author(s) -
Hlavackova Veronika,
Goudet Cyril,
Kniazeff Julie,
Zikova Alice,
Maurel Damien,
Vol Claire,
Trojanova Johana,
Prézeau Laurent,
Pin JeanPhilippe,
Blahos Jaroslav
Publication year - 2005
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600557
Subject(s) - g protein coupled receptor , biology , receptor , metabotropic receptor , protein subunit , class c gpcr , hek 293 cells , agonist , microbiology and biotechnology , rhodopsin like receptors , g protein , inverse agonist , metabotropic glutamate receptor , biochemistry , biophysics , gene
G‐protein‐coupled receptors (GPCRs) have been shown to form dimers, but the relevance of this phenomenon in G‐protein activation is not known. Among the large GPCR family, metabotropic glutamate (mGlu) receptors are constitutive dimers. Here we examined whether both heptahelical domains (HDs) are turned on upon full receptor activation. To that aim, we measured G‐protein coupling efficacy of dimeric mGlu receptors in which one subunit bears specific mutations. We show that a mutation in the third intracellular loop (i3 loop) known to prevent G‐protein activation in a single subunit decreases coupling efficacy. However, when a single HD is blocked in its inactive state using an inverse agonist, 2‐methyl‐6‐(phenylethynyl)pyridine (MPEP), no decrease in receptor activity is observed. Interestingly, in a receptor dimer in which the subunit that binds MPEP is mutated in its i3 loop, MPEP enhances agonist‐induced activity, reflecting a ‘better’ activation of the adjacent HD. These data are consistent with a model in which a single HD is turned on upon activation of such homodimeric receptors and raise important issues in deciphering the functional role of GPCR dimer formation for G‐protein activation.